Mne Lect 23 - Insulinoma

Front 1

Insulinoma (basic definition)

Back 1

-functional pancreatic insulin secreting tumor
-islet cell tumor, beta cell tumor
-uncommon endocrine problem
- unregulated production of insulin
- Classic manifestation of an insulinoma is hypoglycemia, but insulinoma is NOT the same as hypoglycemia!

Front 2

BE SURE TO READ DYNAMED ON INSULINOMA BEFORE EXAM

Back 2

!

Front 3

DO THE CLINICAL CORRELATE QUESTIONS BEFORE EXAM

Back 3

!

Front 4

Effects of insulin on glucose metabolism

Back 4

1. Increases glucose transport into fat and muscle
2. Increases glycolysis (glucose disposal by conversion into pyruvate) in fat and muscle
3. Stimulates glycogen synthesis
4. Inhibits glycogenolysis and gluconeogenesis

Front 5

Actions of insulin on fat, ketone body, and protein metabolism

Back 5

1. Promotes storage of triglyceride in fat cells
2. Inhibits lipolysis of stored triglycerides
3.Inhibits ketogenesis in the liver
Increases peripheral clearance of ketone bodies
4. Increases nitrogen retention and protein storage

Front 6

Causes of hypoglycemia

Back 6

-Commonly seen in sick or hospitalized patients
-Causes include:

a. drugs, including insulin* and sulfonylureas* and meglitinides*

b. hepatic failure

c. chronic renal failure
-kidneys important for gluconeogenesis

d. sepsis

e. malnutrition
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f. Endocrine Disorders
1. Hormonal deficiencies
-Adrenal insufficiency (Not enough cortisol)
-Severe hypothyroidism
-Growth hormone deficiency
-Hypopituitarism

2. Hormonal excesses
-Insulin secreting adenoma or carcinoma (insulinoma) -- Rarest cause
-Islet cell hypertrophy

Front 7

Drugs that can cause hypoglycemia

Back 7

1. Insulin*
2. Sulfonylureas and meglitinides*
--> Oral medications used to treat type II diabetes
3. Alcohol
4. Beta-adrenergic antagonists
5. Angiotensin-converting enzymes inhibitors
6. Salicylates
7. Quinine
8. Haloperidol
9. Disopyramide
10. Pentamidine
11. Bactrim (when used in renal failure)

Front 8

How does sulfonylurea work?

Back 8

Sulfonylureas and meglitinides*
--> Oral medications used to treat type II diabetes

Schematic of the b-cell showing the potassium channel and the way that these sulfonylureas this class of agents we use to treat type II diabetes is that there is a receptor on the potassium channels, don't know what the endogenous ligand for the receptor is but sulfonylureas work on this receptor and act on the potassium channel to result in depolarization, calcium influx into the cell and insulin secretion

Front 9

When blood sugar drops, what happens? What is the hormonal response to this drop in blood sugar?

Back 9

1. insulin secretion drops**not an increase in a hormone but a decrease
-then you begin to see counter-regulatory hormones that begin to release glucose

Front 10

Symptoms of hypoglycemia

Back 10

Adrenergic
-sweating
-feeling warm
-anxiety
-tremor
-nausea
-palpitations
-tachycardia
-hunger


Neuroglycopenic
-fatigue
-dizziness
-headache
-visual disturbances
-drowsiness
-difficulty speaking
-inability to concentrate
-unusual behavior
-loss of memory, confusion
-loss of consciousness
-seizures

Front 11

How can you tell if a patient’s symptoms caused by hypoglycemia?

Back 11

Whipple’s triad is the key:
-serum glucose < 50 mg/dl
-neuroglycopenic symptoms
-relief of symptoms by raising glucose level

Basically you're asking:
1. Does the patient have a low blood sugar?
2. Are the symptoms associated to low blood sugar?
3. Can you relieve symptoms by raising blood sugar?

Front 12

Who needs evaluation for hypoglycemia?

Back 12

1. Any patient with serum glucose less than 45 - 50 mg/dl and symptoms

**Patients with symptoms of hypoglycemia and normal serum glucose at the same time need NO further evaluation
-->Can give patients a blood glucose meter to check blood sugars so they can see at the time they have those symptoms they have normal blood sugar

Front 13

How do you determine the cause of hypoglycemia?

Back 13

Determination of cause of hypoglycemia: need to confirm they do have low blood sugar

1. rule out common things first
A. Exclude medications
-->Make sure it isn’t something that cant be fixed by changing patient’s medications

B. Rule out hormonal deficiencies
-cortisol
-thyroid hormone

C. Rule out hormonal excesses
-Insulin

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72 hour (or 48 hour) fast is the standard test for the diagnosis of insulinoma (rare)
- Gold standard test to see if patient has insulinoma
-Trying to assess role of insulin in that person’s hypoglycemia
-Observe patient in hospital

Front 14

How is an insulinoma confirmed?

Back 14

An insulinoma is confirmed by demonstrating inappropriately high endogenous insulin levels during spontaneous hypoglycemia

Front 15

Protocol for 72-hour fast

Back 15

72 hour (or 48 hour) fast is the standard test for the diagnosis of insulinoma (rare)
- Gold standard test to see if patient has insulinoma
-Trying to assess role of insulin in that person’s hypoglycemia
-Observe patient in hospital

1. Record the onset of the fast (often after dinner), during the fast the patient can drink calorie-free and caffeine-free beverages

2. Measure BG frequently. When BG < 60 mg/dl, then measure plasma insulin, C–peptide, and proinsulin

3. End the fast when 72 hours have elapsed, or BG < 45 mg/dl and patient has symptoms and/or signs of hypoglycemia

At end of fast :
1. Correlate plasma glucose with insulin, proinsulin, and C-peptide levels

2. Screen for the presence of sulfonylureas or meglitinides
-->A proportion of patients are taking these medications, need to investigate this also as a cause of hypoglycemia

Front 16

How do you determine the results from a 72 hour fast?

Back 16

Criteria for hypoglycemia caused by excess endogenous insulin are:
- Insulin high (> 6 µU/ml (RIA))
- C-peptide high (> 200 pmol/L)
- Proinsulin high (> 5 pmol/L)


This table shows 4 potential outcomes of a 72 hour fast 
1. patient who does NOT have an insulinoma
--> don’t need to do anything further b/c patient maintained normal blood sugar
-->Normal subjects
a. Glucose usually stays above 55 mg/dl
b. Subjects remain without symptoms
c. Insulin, proinsulin, C-peptide levels fall appropriately

2. what we’d expect if someone has an insulinoma --> drop glucose, become symptomatic, accompanying low glucose level see HIGH linsulin, c peptide, and proinsulin --> inappropriate production of insulin at time patient has low blood glucose --> also measure sulfonlyurea.. If they have insulinoma, will be negative
-Patients with an insulinoma:
a. Glucose levels fall below 45 mg/dl
b. Patient become symptomatic
c. Insulin, proinsulin, and C-peptide levels remain inappropriately high

3. Patient who drops blood glucose, have symptoms, see high levels of insulin, c pep, and proinsulin BUT they have sulfonyl-urea in blood stream. This is hypoglycemia due to sulfonyl urea use

4. Low blood glucose w symptoms, insulin is high but c peptide and proinsulin is low. This is not patient making own insulin rather patient is taking insulin

Front 17

What do proinsulin levels look like in a normal patient in response to a 72 hour fast?

Back 17

Graph showing proinsulin levels at beginning and end of fast. Basically all patients have a drop in their proinsulin levels.

Front 18

Which patients have insulinomas and which ones don't? How can you tell?

Back 18

. Here is patients that do not have an insulinoma, have high proinsulin levels that drop by the end of the fast. And then there is group of patients that DO have an insulinoma; these patients have high proinsulin levels at the beginning and then maintain high proinsulin levels at the end.

Front 19

Is the 72 hour test a good test for insulinomas?

Back 19

This is a good test for insulinomas
-this is a number of patients who have a diagnosis of insulinoma and the x axis shows the duration of the 72 hour fast
-On left are the number of patients becoming symptomatic during that fast
- By 36 hours, 75% of patients with insulinoma have dropped their blood sugar and become symptomatic. By the time you get to 72 hours, 98-99% of patients with insulinoma have dropped their blood sugar and have become symptomatic

Front 20

How do insulinoma patients present?

Back 20

Clinical characteristics
1. Fasting hypoglycemia (reduced hepatic glucose output)
2. Neuroglycopenic symptoms
3. Inappropriately high insulin levels

Front 21

At what age are patients often diagnosed with insulinomas? Mean duration of time with symptoms prior to diagnosis? Are they commonly misdiagnosed?

Back 21

- mean age at the time of diagnosis is 47 years

- mean duration of symptoms before diagnosis 1.5 yrs

- as many as 20% patients are misdiagnosed with a neurologic or psychiatric disorder

Front 22

What is the incidence of insulinoma? What percentage are malignant/benign? Recurrence rate? Long term survival??

Back 22

-Incidence: 4 cases per million per year

-87% single, benign
*most are caused by a single, benign tumor

-6% malignant

-7-21 % recurrence

-normal long-term survival, except in patients with malignant insulinomas

Front 23

How do you localize an insulinoma?

Back 23

Tumor localization by pancreatic imaging
a. Spiral CT scan
b. MRI
c. Transabdominal ultrasound
d. Endoscopic ultrasound

Front 24

How do you treat an insulinoma?

What do you observe following treatment?

Back 24

1. Surgical resection treatment of choice
-The first surgical cure of insulinoma was reported in 1929 by Howland
- 90-95% successful cure with single benign adenoma when intraoperative ultrasound is used
-Laparoscopic approach feasible in some patients
-Small tumors can be enucleated
(popped out without much of the pancreas being resected )
-Larger lesions require partial pancreatic resection
-Whipple procedure (partial pancreatectomy, duodenectomy) is rarely required, usually only in cases where tumor is in the high value real estate region -- blood flow

2. Medical management
-Not as effective as surgery
-Used only for patients who are not surgical candidates
- Potential therapies
a. Diazoxide: inhibits release of insulin by beta cells
b. Octreotide; somatostatin analogue
c. Interferon-alfa (manmade protein copy of interferon-alpha)
d. Verapamil

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FOLLOWING SURGERY
- Within minutes of insulinoma excision blood glucose rises to 120 - 140 mg/dl range
- May get transient post-operative hyperglycemia (200 - 250 mg/dl), which usually resolves by 48 - 72 hours

Front 25

GO BACK TO POWERPOINT AND REVIEW SLIDES 42-69 for 2 CASE EXAMPLES

Back 25

GO BACK TO POWERPOINT AND REVIEW SLIDES 42-69 for 2 CASE EXAMPLES